Method and formulations for the treatment of obesity

ABSTRACT

It has been discovered that the unfavorable effects observed in weight reduction treatments based on severe dietary restriction (less than 600 Kcals/day) or total fasting (as regards fat, carbohydrates and aminoacids) are avoided by the administration of aminoacids and carbohydrates in critical but much lower amounts than has been believed to be necessary. Nitrogen loss with aminoacid intake between about 15 g and 30 g per day is affected by carbohydrate intake. Nitrogen balance is maintained and ketosis and water retention are controlled when the daily intake includes, in addition to necessary minerals and vitamins, at least 15 g of aminoacids in the proportions required by man, and from 15 g to 75 g, preferably 30 g to 45 g, of carbohydrates, with a total caloric value of from 160 to about 600 Kcals, preferably less than 400 Kcals, very desirably less than 360 Kcals, and optimally in the range of from 180 to 360 Kcals. Formulations are described in which the least amount containing the minimum daily requirement of minerals also contains at least 15 g of aminoacids (as a monomeric aminoacid mixture or as natural protein) and from 15 g to 75 g, preferably from 30 g to 45 g, of carbohydrates, together with optional other constituents.

This is a continuation of application Ser. No. 693,599, filed June 7,1976, now abandoned which is a division of Ser. No. 338,257, filed Mar.5, 1973, now U.S. Pat. No. 4,009,265.

This invention relates to methods and formulations for the treatment ofobesity.

BACKGROUND OF THE INVENTION

When it is required to bring about weight reduction in over-weightpatients, it is naturally necessary to reduce their food intake, sincethe object of the weight-reduction treatment is to cause the body toconsume its own fatty tissues in meeting its energy requirements. Tothis end, it has hitherto been necessary for the diet of the patients tobe very strictly controlled and supervised during the period ofweight-reduction, which might extend to several months. To exercise socomplete a control over the patient's diet it is most convenient toincorporate all the food requirements of the patients into a singledietary composition, and this has been the normal practice.Unfortunately, such controlled diets have hitherto been veryunsatisfying, and the patients feel constantly hungry, which is ofcourse very unpleasant. This causes many patients to break off the diet;and even those patients who are motivated sufficiently strongly to staythe course often find that the diet is almost intolerable.

Furthermore, many physiological and psychological problems have hithertobeen associated with the clinical use of severe dietary restriction. Oneof these problems arises from the fact that the body requires a constantsupply of nitrogen (in the form of aminoacids or their polymers) toreplace the endogenous nitrogen losses resulting from the normal "wearand tear" of the body's protein. If an adequate amount of aminoacids isnot supplied there is a loss of body protein, with consequent reductionin muscle mass; this leaves the patient feeling weak and languid. Ifthis protein loss continues for too long it can be dangerous, and eventhe heart muscle may suffer damage. In fact, this loss of muscle mass isone of the main reason why total fasting is not favoured as aweight-reduction treatment.

Accordingly, sufficient aminoacids must be provided in the diet toprevent serious endogenous nitrogen loss. It has been thought, up tonow, that to avoid the consequences of serious endogenous nitrogen lossit is necessary to supply the patient with about 40 g to about 65 g ofprotein per day--see for example "Human Nutrition and Dietetics", byDavidson, S. and Passmore, R., 4th Edition (1969) published by E. & S.Livingstone, Edinburgh, page 85.

Another problem arising with complete starvation, and with someconventional diets, is that the blood uric acid level rises greatly,which may lead to gout.

Yet another problem arises from the obvious fact that, during dieting,the body must of course break down and consume its own fatty tissues tomeet its energy requirements, and will do so only if its calorie intakeis very severely restricted. However, in the absence of sufficientcarbohydrate, the catabolism of fatty acids leads to a build-up ofketonic waste-products in the body, leading to a condition known as"ketosis". Severe ketosis gives rise to psychological disturbances suchas depression and irritability, and has other unpleasant side-effectsincluding acidosis and nausea. Despite the disadvantage from aweight-loss viewpoint, it is therefore necessary to include carbohydratein the diet so as to reduce the level of body ketones and thus avoidsevere ketosis--as well as also reducing the blood uric acid level, thuslessening the likelihood of gout. Till now it has however been thoughtthat at least about 100 g of carbohydrate per day is needed if ketosisis to be completely prevented (see "Human Nutrition and Dietectics", byDavidson, S. and Passmore, R., 4th Edition (1969), page 127) and this isalso considered to prevent a rise in blood uric acid level. Someconventional diets in fact give the patient as much as 400-500 g/day ofcarbohydrate.

If one tries to avoid the problems caused by the absence of sufficientcarbohydrate by using instead a low-calorie diet in which a relativelylarge percentage of the total calories is derived from carbohydrates,then the body tends to retain a considerable amount of water in itstissues. Although this is not desirable, it could be tolerated withinreason by the clinician, since the retained water will be largely shedwhen the patient resumes a normal diet--but it has an adverse effect onthe patient, since his weight due to water retention remains almostconstant while on the diet, which is frustrating to the patient who cansee no visible signs of the diet achieving its purpose. Moreover thiswater-retention cannot be tolerated even by the clinician beyond acertain point, since it leads to edema. The patient is losing fat, buthis tissues are retaining about the same weight of water, and if thiscontinues for a prolonged period, edema results and fluid collectsaround the ankle joints.

Previous research has revealed the existence of the problems outlinedabove, but has found no way of resolving the apparently conflictingrequirements of patients for carbohydrates during dieting. It has simplybeen assumed that in order to prevent catabolism of aminoacids thepatient must be supplied with a fairly large quantity of carbohydrates.

SUMMARY OF THE INVENTION

It has now been discovered in experimental trials with obese patientsthat, provided the carbohydrate intake of the patient is at least about30 to about 45 g/day, the amount of aminoacids required to maintainoverall nitrogen equilibrium is only about 15-25 g/day--about one-thirdto one-half of the amount previously thought necessary. If thecarbohydrate intake is below about 30 g/day, larger amounts ofaminoacids are required. For example, if the carbohydrate intake isreduced to 15 g, the aminoacid requirement for nitrogen equilibriumrises above 25 g. At these carbohydrate intakes, water retention isabsent or minimal. When the carbohydrate intake is increased above about45 g/day water retention begins to be observable, and with amounts aboveabout 75 g/day the water retention may be severe enough to be diagnosedas clinical edema.

In the light of the above discoveries it can be seen that conventionaldiets for the treatment of obesity are far from ideal. Theseconventional diets are usually prepared from normal food ingredientsselected to be of high protein content, but relatively low in fat andcarbohydrate. The nutrient balance of the preparations may be furtheradjusted by blending in other food ingredients such as specific proteinsisolated from foodstuffs, vitamins and minerals. Since a diet consistingof protein with some carbohydrate and fat is not very bulky,non-calorific substances, such as cellulose and methyl cellulose orsimilar materials, are sometimes added to provide bulk and hence give afeeling of satiety.

Usually such conventional diets will give a protein intake of about40-60 g/day or more and a carbohydrate intake in excess of 100 g/day,but so balanced and supplemented with fats as to supply 900-1200Kcals/day. Thus these conventional diets supply far larger quantities ofprotein and carbohydrate than the minima now discovered to be necessary.As previously indicated such conventional formulations suffer from thedisadvantages that they cause retention of body water due to their highcarbohydrate content, and that they are high in calories, thus slowingdown the rate of weight loss. In addition, many of them contain theessential and non-essential aminoacids in the wrong proportions.

There are other commercially-available food preparations which are notspecifically intended for the treatment of obesity, but which do containaminoacids present in substantially the proportions required byman--these however all contain more carbohydrate than the above-mentonedoptimum.

For instance, one such known preparation intended for administration topatients who are to undergo intestinal surgery contains aminoacids andcarbohydrate in a weight ratio of about 1:10. If this preparation wereused during severe dietary restriction to treat obesity, in order tosatisfy the minimum requirement of protein now found to be necessary itwould have to be given at a rate of about 165 g/day, thus giving 15g/day of protein and 150 g/day of carbohydrate, equivalent to about 660Kcals. Apart from the previously-discussed water-retention effectssencountered with an excessive proportion of carbohydrate content, theuse of such a high-calorie preparation also decreases the rate at whichweight is lost.

Another known, commercially-available food preparation sold as anall-in-one breakfast substitute contains the minerals and essentialaminoacids in the proportions required by man as well as carbohydrateand most of the necessary vitamins. Only the dry mixture however has anysimilarity to the dietary formulations of this invention, and even thenits carbohydrate content is so high as to give rise to clinical edemasupposing it were used as a sole foodstuff--while when used inaccordance with the directions, admixed with the suggested amounts ofmilk, its calorie value would be far too high for use in the dietarymethods and formulations of the present invention.

It is an object of this invention to provide a dietary method andformulation for the treatment of obesity in man which takes account ofthe newly-discovered minimum requirements of the patient for aminoacidsand carbohydrate and which thus overcomes the disadvantages of the dietsand preparations known in the prior art.

Accordingly, this invention provides a dietary formulation for thetreatment of obesity in man, which comprises:

(a) all the minerals required by man; and

(b) proteinaceous material selected from at least one member of theclass consisting of:

(i) a mixture of monomeric L-aminoacids, and

(ii) natural proteins, and

(iii) natural proteins reinforced with at least one monomericL-aminoacid;

and (c) digestible carbohydrate;

characterized in that the smallest amount of the dietary formulationcontaining at least the minimum daily requirements of each of theminerals required by man also contains:

(A) at least 15 g of said proteinaceous material which must include atleast the minimum daily requirements for man of all the essentialL-aminoacids required by man; and

(B) from 15 g to 75 g of said carbohydrate;

and further characterized in that the total caloric value of saidsmallest amount of the dietary formulation is in the range of from 160Kcals to 600 Kcals.

The minerals required by man are sodium, potassium, calcium, magnesium,manganese, iron, copper, zinc, chloride, phosphorus, sulfur, iodine andother trace elements. These minerals could theoretically be supplied inthe form of tablets separate from the other ingredients of theformulation of this invention; but the mineral requirements of manamount to about 20 g/day, which in practice is too much to giveconveniently in the form of tablets, and anyway the minerals alone arevery unpleasant to take, and tend in some patients to act as emetics.Accordingly the formulations of this invention already incorporate theminerals required by the patient. The minerals which are likely to bedeficient in any dietary formulation and which must therefore bemonitored with particular care are those listed below, with theirminimum daily requirements, as follows:

    ______________________________________                                        MINIMUM DAILY                                                                 REQUIREMENTS OF MINERALS FOR MAN                                              ______________________________________                                               Calcium 800 mg                                                                Phosphorus                                                                            800 mg                                                                Iodine   140 μg                                                            Iron     10 mg                                                                Magnesium                                                                             350 mg                                                         ______________________________________                                    

Other mineral requirements must naturally also be met, for instancesodium and potassium, as will be well-known to those skilled in theart--but in general it should be found that trace elements are suppliedin sufficient amount without special attention being paid to them.

The proteinaceous material used in the dietary formulations of thisinvention can be supplied either in the form of a mixture of monomericL-aminoacids or in the form of natural protein--or perhaps in the formof the latter reinforced with at least some of the former. Preferablythe aminoacids will be present as monomeric L-aminoacids, since it isthen easier to adjust the aminoacid profile to achieve the optimumnitrogen utilization; it will be appreciated that any deviation from theoptimum aminoacid profile either leaves the body short of certainaminoacids--with consequent serious disturbances in proteinmetabolism--or forces the body to make the required aminoacids fromother aminoacids, which is a rather inefficient process. In either case,more of the aminoacid mixture is then required by the patient.

The preferred compositions of this invention are those in which all theL-aminoacids, i.e. both the essential and the semi-essential ones, arepresent in the relative proportions required by man. The aminoacidprofile essential to man is well-known to those skilled in the art, andfor example is set out in Rose, W. C., Wixom, R. L., Lockhart, H. A.,Lambert, G. F., J. Biol. Chem., (1955), 217, page 987. The optimumprofile is also illustrated by the formulation described in detailbelow. The L-aminoacids useful to man are isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan, valine (those beingthe so-called essential aminoacids), together with alanine, arginine,aspartic acid, cystine, glutamic acid (or glutamine), glycine,histidine, hydroxyproline, proline, serine and tyrosine (the so-callednon-essential or semi-essential aminoacids).

Where the formulation of this invention contains monomeric L-aminoacids,a convenient and cheap method of producing the required aminoacidmixture is to take a protein hydrolysate (produced by any conventionalprocedure, such as by subjecting a protein to hydrolysis using an acidor a proteolase as the hydrolytic agent--various such proteinhydrolysates are available commercially) analysing its aminoacid profileand adjusting to the optimum profile, either by adding the requiredquantities of the pure aminoacids to make up for any deficiencies and/orby passing the hydrolysate through suitable combinations of anionic andcationic exchange resins (these being already well-known) to eliminateany excesses.

On the other hand, where the dietary formulation contains the aminoacidsin the form of natural protein, this most conveniently will be eggprotein, since this already contains aminoacids in the relativeproportions required by man (see Davidson, S. and Passmore, R., "HumanNutrition and Dietetics", E. & S. Livingstone, (1969), page 80).

However, despite being deficient in one or more aminoacids, otherproteinaceous materials may also be employed, preferably for instancesuch proteinaceous materials as those derived from milk, soya beans,peanuts, fish and plasma proteins. When such aminoacid-deficientproteins are used, it is necessary either to add the appropriateaminoacids to adjust the profile accordingly, or to give an excess ofprotein such that the minimum requirements of even the most deficientaminoacid are met.

The carbohydrate in the formulation of this invention can be anydigestible carbohydrate such as a readily absorbable monosaccharide, forexample glucose, glucose-δ-lactone, fructose or lactose, di-saccharidessuch as sucrose or maltose, or a polysaccharide, for example ediblestarch or dextrin. However, a dietary formulation containing largequantities of mono- and di-saccharides tends to have undesirableside-effects. Pure mono- and di-saccharides are very sweet and somepatients find a dietary formulation containing them highly unpalatable.In addition, mono- and di- saccharides, because of their high osmoticpressure, tend to induce nausea and their rapid absorption into theblood stream leads to sudden large increases in blood sugar, with theconsequent risk of insulin rebound and hypoglycemia. Thus, it ispreferred that the carbohydrate used in the dietary formulation of thisinvention be partially hydrolysed poly-saccharides, since these do notsuffer from the undesirable effects associated with mono- anddi-saccharides. The preferred partially hydrolysed polysaccharides arethose oligo-saccharides having an average molecular weight (asdetermined by osmosis) of from 3 to 10 times that of the correspondingmonomer, the optimum molecular weight being 4 to 6 times that of themonomer. Dextrose oligosaccharides are especially suitable. Theoligosaccharides can conveniently be used as the only source ofcarbohydrate or alternatively mixed with a proportion of mono- ordi-saccharide; a mixture of 1 part mono- or di-saccharide with fromabout 3 to about 5 parts by weight of oligosaccharide is suitable.

Further to illustrate the invention, some of the most importantparameters of the dietary formulation are shown in the accompanyingdrawings, in which:

FIG. 1 is a graphical representation of the absolute and relativeamounts of carbohydrate and proteinaceous material in the dietaryformulation on a per diem basis, wherein the grams of carbohydrate givenper day are plotted along the ordinate, while the grams of proteinaceousmaterial given per day are plotted along the abscissa.

In FIG. 1, the dietary formulations of the invention are those lyingwithin the pentagon ABCDE. The line AE represents the minimum of 15 gmprotein per day; any dietary formulation or other food preparation lyingto the left of this line contains insufficient protein, and causesendogenous nitrogen loss in the patient.

The lines AB and DC represent respectively the maximum of 75 gm per dayof carbohydrate and the minimum of 15 gm per day of carbohydrate. Above75 gm/day, severe water-retention problems are encountered, so thatweight loss is retarded, and edema may set in; whilst below 15 gm/day ofcarbohydrate, severe problems are encountered with ketosis.

The line BC represents the upper limit of 600 Kcals/day, which is theline below which the patient can be regarded as undergoing the severedietary restriction with which this invention is concerned, and whichdifferentiates it completely from conventional dietary regimes. However,to achieve the rapid weight losses which are desired, it it greatlypreferred to limit the calorie-intake to less than 400 Kcal/day, and thebest results are secured below an upper limit of 360 Kcals/day. The lineED represents the absolute lower limit of 160 Kcals/day, below which itis no longer possible to maintain the patient's nitrogen equilibrium.Between these upper and lower limits, the preferred range of calorieintake on a balance of all considerations, is in the range of from 180to 240 Kcals/day.

On the graph of FIG. 1 there have also been plotted lines representingweight ratios of proteinaceous material to carbohydrate ranging from 1:1up to 1:5.

The ratio of aminoacids to carbohydrates in the dietary formulations ofthis invention must not decrease below 1:5, since then the dietaryformulation is too high in calories, thus reducing the rate of weightloss, while the problems of fluid retention mentioned above become verysevere. Preferably the ratio of aminoacids to carbohydrates will notexceed about 1:1, since clinical tests have shown that if that ratioincreases above about 1:1 then the tendency to ketosis sets in andbecomes increasingly severe--while anyway, such formulations areexpensive, since they contain a high proportion of the relatively-costlyaminoacids.

The optimum daily intake for the patient is about 15 to about 25 gaminoacids and from about 30 to about 45 g carbohydrate. As statedabove, however, the ratio of aminoacids to carbohydrate in the dietaryformulations of this invention preferably lies in the range of fromabout 1:1 to about 1:5, and it is especially preferred that it lie inthe range of from about 1:2 to about 1:4, most desirably in the range offrom 1:2 to 1:3.

Within these parameters it is possible for the patient to be given thepreferred low calorie intake of 180-240 Kcalories/day. At that low rateof intake, ketosis is at most vary moderate, and certainly such that theabove-mentioned unpleasant side-effects of severe ketosis arenegligible.

An unexpected advantage of the dietary formulations of this invention isthe absence of physical distress such as hunger. Although the precisereason is not known, it is possible that the presentation of thesevarious nutrients as aminoacids and as simple carbohydrates and/orpolysaccharides may affect alimentary secretions and preistalsis,thereby suppressing hunger. As a consequence of the good physicalcondition of the patients and the absence of distress, they remain in agood psychological state with little desire to cheat or to depart fromthe diet until the desired weight loss has been achieved.

Vitamins in the amounts needed by the patient may be administeredseparately from the other dietary ingredients, since unlike mineralsthere are no problems of bulk or nausea with vitamins. It is howevergenerally most convenient if the necessary vitamins are incorporated inthe formulation with the other constituents. As is well-known to thoseskilled in the art, the essential vitamins are vitamin A (either as suchor as carotene), vitamin B₁₂ (cyanocobalamin), vitamin C (ascorbicacid), vitamin D(eg. calciferol), vitamin E (tocopherol), vitamin K (or2-methyl-1:4-naphthoquinone), para-aminobenzoic acid (preferably givenas the potassium salt), riboflavin, pyridoxin, niacin, inositol, calciumpantothenate, biotin, folic acid, choline and thiamin hydrochloride. Theso-called minimum daily requirements of man for each of these vitaminsare well-known (though there is som disparity between the standardsestablished in different countries) and may be found in any standardwork on nutrition, such as for example "Human Nutrition and Dietetics",by Davidson, S. and Passmore, R., 4th Edition (1969) published by E. &S. Livingstone, Edinburgh, pages 244 and 255.

The accepted minimum daily requirements of man for the most important ofthe vitamins are set out below, as follows:

    ______________________________________                                        MINIMUM DAILY                                                                 REQUIREMENTS OF VITAMINS FOR MAN                                              ______________________________________                                        Ascorbic acid (Vitamin C)                                                                             60 mg                                                 Folic acid              0.4 mg                                                Niacin                  18 mg                                                 Riboflavin              1.7 mg                                                Thiamin                 1.4 mg                                                Vitamin A               5000 i.u.                                             Vitamin B.sub.6         2.0 mg                                                Vitamin B.sub.12        5.0 μg                                             Vitamin D               400 i.u.                                              Vitamin E                30 i.u.                                              ______________________________________                                    

The minimum daily requirements for the other essential vitamins are sominimal as to be difficult to establish with certainty, and thereforehave not been laid down precisely. The currently accepted levels can beadhered to by following the recommendations in the dietary formulationdescribed in detail hereinafter.

Even when subjected to dietary restriction, man requires certain amountsof fat, oil or other source of essential fatty acid. This fat or oil maybe given separately; but for general convenience it is much preferredthat the formulation should also contain enough fat or oil to supply atleast the minimum requirements of the patient for essential fatty acids.The amount of oil and fat required by man is subject to someuncertainty--but following "Human Nutrition and Dietetics" (loc. cit.)page 112, it may be assumed to be from about 2.4 to about 3.8 g./day.The preferred fats/oils are highly-unsaturated vegetable oils,especially those having a high content (≧25%) of linoleic acid, such asfor example safflower seed oil or ethyl linoleate. The formulationtherefore will normally contain at least about 3% by weight and not morethan about 10% by weight of safflower oil or equivalent.

The dietary formulations may contain a bulking component, for examplecellulose or methyl cellulose or a gum such as acacia gum, tragacanthgum, guar gum or xanthan gum. The amount of any such bulking componentswill usually be small, say less than about 10% by weight of theformulation, but can in some cases amount to 50% or even more. Thedietary formulation may also contain an emulsifier of the kindrecommended for use in foodstuffs, for example polyoxyethylene sorbitanmono-oleate, and can also incorporate flavouring agents to increasepalatability.

This invention also provides a method for the treatment of obesity inman, which comprises the steps of giving the overweight patient a dailydiet consisting essentially of:

(a) at least the minimum daily requirement of all the minerals requiredby man;

(b) proteinaceous material selected from at least one member of theclass consisting of:

(i) a mixture of monomeric L-aminoacids, and

(ii) natural proteins, and

(iii) natural proteins reinforced with at least one monomericL-aminoacid;

(c) digestible carbohydrate;

(d) at least the minimum daily requirement of all the vitamins requiredby man; and

(e) sufficient fat, oil or other source of essential fatty acid tosupply the patient's minimum fatty acid requirements;

said method being characterised in that the amount of proteinaceousmaterial given daily is at least 15 g. and contains at least the minimumdaily requirements for man of all the essential L-aminoacids required byman, and the amount of carbohydrate given daily in from 15 g to 75 g,and that the total caloric value of the daily diet is in the range offrom 160 Kcals to 600 Kcals.

The upper limit of 600 Kcals/day represents the dividing line betweenthe severe dietary restriction with which this invention is concernedand conventional dietary regimes. However, to achieve the rapid weightlosses which are desired it is greatly preferred to limit thecalorie-intake to less than 400 Kcals/day, and for most purposes anupper limit of not more than 360 Kcals/day will be appropriate. Belowthe absolute lower limit of 160 Kcals/day it is no longer possible tomaintain the patient's nitrogen equilibrium. Between these upper andlower limits, the preferred range of calorie intake, on a balance of allconsiderations, is in the range of from 180 to 240 Kcals/day. Theminerals will preferably be given is substantially the relativeproportions required by man. The ratio by weight of the proteinaceousmaterial to the digestible carbohydrate in the diet should desirably bein the range of from 1:2 to 1:4, and most desirably between 1:2 and 1:3.

The proteinaceous material in the diet will advantageously consist of orinclude egg albumin, but other proteinaceous materials can be used suchas natural protein derived from milk, soya beans, peanuts, fish and/orplasma, preferably reinforced with at least one monomeric L-aminoacid toadjust its aminoacid profile to that required by man. Alternatively, theproteinaceous material may be a mixture of aminoacids produced by takinga protein hydrolysate (produced by subjecting a protein to hydrolysis byan acid or a proteolase) analysing its aminoacid profile and adjustingto the optimum profile either by adding the required quantities ofaminoacids or by passing the hydrolysate through suitable ion-exchangeresins.

The carbohydrate component in the diet of this invention isadvantageously a partially hydrolyzed polysaccharide, preferably anoligosaccharide having an average molecular weight (as determined byosmosis) of from 3 to 10 times (most desirably 4 to 6 times) that of thecorresponding monomer.

It is necessary that the diet should include at least the minimum dailyrequirements of each of the vitamins required by man, and it is verydesirable that these vitamins should be present in substantially therelative proportions required by man. It is also necessary that the dietshould include at least the minimum daily fatty acid requirements ofman; the fatty acid is preferably present in the form of a highlyunsaturated vegetable oil, most preferably one containing at least 25%of linolenic acid. Desirably, the fatty acid comprises not more than 10%by weight of the diet.

DESCRIPTION OF THE PREFERRED EMBODIMENT

In order that this invention may be more easily understood, thefollowing Examples will now be given though by way of illustration only,to show details of the dietary formulations of this invention and theclinical test results obtained using such formulations in comparisonwith others.

DIETARY FORMULATION

The following Table sets out the ingredients of a dietary formulation ofthis invention which has been proved by clinical trials to be eminentlysuitable for the treatment of obesity in man. For comparison, theingredients of a known dietary formulation, intended for use as anon-residual foodstuff for patients undergoing intestinal surgery or thelike, are also set out. In the dietary formulation of the presentinvention the ratio by weight of L-aminoacid to carbohydrate is 1:2.4,while in the comparison formulation it is approximately 1:10.

It will be seen that the dietary formulation of this invention is muchricher in aminoacids on a percentage basis than the prior artformulation. It is also richer in vitamins and minerals; this is becausethe prior art formulation is intended to be given in amounts of about450 to 650 g/day, whereas the formulation of the present invention isintended to be given in amounts of less than 100 g/day. It should alsobe noted that the formulation of this invention contains dextroseoligosaccharide as the major part of its carbohydrates, whereas thecarbohydrate in the prior art formulation consists primarily of glucose,with a small amount of glucose-δ-lactone.

The dietary formulation of this invention is normally administered inwater, and preferably in amounts of 1 liter or more per day, in 3 to 6divided doses. Thus, the concentration of nutrients in the liquidactually administered would normally be equal to less than 15-25 g/laminoacids and 75 g/l carbohydrate.

                  TABLE 1                                                         ______________________________________                                                       Formulation of                                                                          Formulation of                                                      the present                                                                             the prior                                                           invention art                                                                 (per 1000 g of formulation)                                    ______________________________________                                        Aminoacids                                                                    L-Lysine HCl     10.02 g     5.48 g                                           L-Leucine        13.37 g     5.87 g                                           L-Isoleucine     8.45 g      3.71 g                                           L-Valine         9.31 g      4.09 g                                           L-Phenylalanine  9.63 g      4.21 g                                           L-Arginine HCl   16.40 g     8.73 g                                           L-Histidine HCl H.sub.2 O                                                                      4.10 g      2.42 g                                           L-Alanine        9.02 g      3.95 g                                           L-Aspartic Acid  19.19 g     8.42 g                                           L-Threonine      8.45 g      3.71 g                                           L-Proline        12.04 g     5.24 g                                           Glycine          14.69 g     6.43 g                                           L-Serine         6.19 g      2.71 g                                           L-Tyrosine ethyl ester                                                                         10.54 g     6.28 g                                           HCl                                                                           L-Glutamine      31.69 g     13.89 g                                          L-Methionine     8.65 g      2.68 g                                           L-Tryptophan     2.60 g      1.15 g                                           Total:           194.3 g     88.97 g                                          Salts                                                                         Potassium iodide 1.94 mg     0.23 mg                                          Manganous acetate . 4H.sub.2 O                                                                 237 mg      28.07 mg                                         Cupric acetate . H.sub.2 O                                                                     32.35 mg    3.83 mg                                          Sodium glycerophosphate                                                                        67.7 g      8.0 g                                            Sodium chloride  89.3 g      8.19 g                                           Ferrous ammonium sulphate                                                                      8.83 g      1.04 g                                           Zinc chloride    15.53 mg    1.84 mg                                          Potassium hydroxide                                                                            13.35 g     6.08 g                                           Potassium chloride                                                                             53.1 g       --                                              Magnesium oxide  6.31 g      0.567 g                                          Sodium hydroxide --          2.56 g                                           Calcium chloride . 2H.sub.2 O                                                                  31.57 g     3.74 g                                           Total:           270.6 g     30.18 g                                          Vitamins                                                                      Thiamin HCl      15.5 mg     1.84 mg                                          Riboflavin       22.0 mg     2.60 mg                                          Pyridoxin HCl    21.6 mg     2.56 mg                                          Niacinamide      129.4 mg    15.31 mg                                         Inositol         10.74 mg    1.27 mg                                          d-Ca pantothenate                                                                              181.2 mg    21.50 mg                                         Vitamin A acetate                                                                              64,700 Int. units                                                                         7,700 Int. units                                 Vitamin D.sub.2 -D.sub.3                                                                        5,180 Int. units                                                                           613 Int. units                                 d-Biotin         3.88 mg     0.46 mg                                          Folic acid       21.6 mg     2.56 mg                                          Ascorbic acid    1.035 g     122.5 mg                                         Cyanocobalamin   0.194 mg    23.0 μg                                       p-Amino benzoic acid                                                                           5.380 g     636.0 mg                                         Choline bitartrate                                                                             2.990 g     341.0 mg                                         α-Tocopherol acetate                                                                     388.1 mg    45.9 mg                                          Menadioue (Vit. K)                                                                             776.4 mg    91.9 mg                                          Total:           11.0 g      1.286 g                                          Carbohydrate                                                                  Glucose          54.3 g      849.9 g                                          Glucose-δ-lactone                                                                        --          23.54 g                                          Dextrose oligosaccharides                                                                      418.0 g     --                                               Total:           472.3 g     873.44 g                                         Fats                                                                          Ethyl linoleate  25.9 g      --                                               Safflower oil    --          3.06 g                                           Total:           25.9 g      3.06 g                                           Emulsifier                                                                    Polyoxyethylene                                                               sorbitan monooleate                                                                            25.9 g      3.06 g                                           ______________________________________                                    

Clinical Test Results

Following a period of starvation for two weeks (in which no food exceptvitamins and minerals were given) a series of nine differentexperimental diets were given to human patients each for a period of atleast two weeks as shown in Table 2 (some of the diets were inaccordance with this invention and some were not).

The constitution and amounts of each diet given contained the minimumquantity of aminoacids normally needed to maintain nitrogen balance. Thediets used were simply formulated by mixing the appropriate amounts ofthe aminoacid mixture and carbohydrate together in bulk and then addinga days supply of vitamins and minerals to a daily dose of this bulkmixture.

    TABLE 2                   Effect of     Wt. of          treatment g. g. Aminoacid:     composn. Cals Approximate     Body Psychological  on serum Willingness     amino- carbo- carbohydrate given per weight change     Fluid state of     uric acid to remain acids hydrate wt. ratio (gms/day) day kg/week     Ketosis Cost/Week  Balance patient  level on diet       Control 30 0 1:0 30 120 -1.5 to -3.0  Very High  Diuresis Poor  Raised              severe      significantly Poor lower limit 30 15   1:0.5 45 180     -1.5 to -3.0  Severe High  Diuresis Poor  Raised of carbo-     significantly Poor hydrate Preferred 22.5 22.5 1:1 45 180 - 2.0 to -2.5     Moderate Moderate  No excess- Excellent  Slightly Good Formulations 15     30 1:2 45 180 -1.0 to -2.5  Moderate Moderate ive loss Excellent  Good     of Invention 15 45 1:3 60 240 -1.0 to -2.5  Slight Moderate  or water     Excellent  raised Good            retention   Not Good  15 60 1:4 75 300     -1.0 to -2.5  Very slight Moderate  Slight Good             water     raised Good  15 75 1:5 90 360 -0.5 to -2.0  or absent Moderate  retention      Good  Not raised Good Control 15 90 1:6 105 410 +2.0 to -0.5  Absent     Moderate  Excessive Poor  Not raised Poor Control 15 120 1:8 135 540     +2.0 to -0.5  Absent Moderate  Water Poor  Not raised Poor Control 15     150  1:30 165 660 +2.0 to -0.5  Absent Moderate  retention Poor  Not     raised Poor     Note:     The nature of the aminoacid and carbohydrate components used in these     tests is described below

The aminoacid component used in the tests reported in Table 2 above wasa mixture of monomeric L-aminoacids having the following constitution:

    ______________________________________                                        Essential aminoacids                                                          L-Isoleucine       4.34%                                                      L-Leucine          6.87%                                                      L-Lysine.sup.(1)   5.16%                                                      L-methoinine       4.45%                                                      L-Phenylalanine    4.95%                                                      L-Threonine        4.34%                                                      L-Tryptophan       1.35%                                                      L-Valine           4.79%                                                      Non-essential aminoacids                                                      L-Alanine          4.64%                                                      L-Arginine.sup.(1) 8.48%                                                      L-Aspartic acid    9.88%                                                      L-Glutamine        16.30%                                                     Glycine            7.56%                                                      L-Histidine.sup.(1)                                                                              2.11%                                                      L-Proline          6.18%                                                      L-Serine           3.17%                                                      L-Tyrosine.sup.(2) 5.43%                                                      ______________________________________                                         Notes:-                                                                       .sup.(1) Present in diet as the monohydrochloride;                            .sup.(2) Present in diet as the ethyl ester monohydrochloride.           

It should however be noted that the same tests have also been conducted,with the aminoacid/carbohydrate ratios of from 1:1 up to 1:5, using thefollowing other proteinaceous materials, namely:

(a) Purified precipitate of calcium salts of milk

Protein--100 g

L-Methionine--2 g

and (b) Egg albumin

The results obtained using these other proteinaceous materials were thesame as when using the monomeric L-aminoacid mixture.

The carbohydrate used in the tests reported in Table 2 was in most casespure dextrose oligosaccharide, though in some instances a smalladmixture of glucose was also present.

The advantages and disadvantages of the diets having variousaminoacid:carbohydrate ratios, some inside and some outside those of theinvention, may be summarized as follows:

The weight losses secured with an aminoacid: carbohydrate ratio of 1:0were good, though much of this was due to excessive loss of body water.Ketosis on the other hand was very severe, serum uric acid level wasraised, and the psychological condition of the patient was poor - sopoor that it was difficult to persuade the patients to remain on thediet because of irritability and aggressiveness. Moreover, withnegligible carbohydrate content, the quantity of expensive aminoacids inthe diet to maintain nitrogen balance was greatly increased, making thediet unduly costly.

At the other end of the scale, with aminoacid: carbohydrate ratios ofgreater than 1:5, there was no ketosis, no effect on serum uric acidlevel, and the cost of the diet was moderate. On the other hand, theweight losses secured were poor, and indeed patients often gainedweight, due to water retention. Moreover, the failure to lose weightcaused the psychological state of the patients to be poor and it wasdifficult to persuade them to continue on the diet.

However, when the aminoacid:carbohydrate ratio was 1:0.5 ketosis was nolonger very severe; and within the preferred limits of from 1:1 to 1:5high rates of weight-loss were secured while the psychological conditionof the patient remained excellent. Ketosis was very moderate to slight,and the blood serum uric acid level was not raised by this treatment.Encouraged by their satisfactory weight loss and absence of hunger, thepatients were willing to continue on the diet for long periods. Theirgeneral health was good, and they all remained ambulatory. It can beseen that the best diets were those having ratios of from 1:2 to 1:3.

The data shown in Table 2 also demonstrates that ketosis becomes verysevere when the absolute amount of carbohydrate in the diet drops below15 g./day; while water-retention becomes excessive (and indeed clinicaledema sets in) when it exceeds 75 g./day. Similarly it can be seen thatthe best results in terms of weight-loss and a balance of other factorsare clearly secured at calorie-intakes of from 180-360 Kcals/day, andthe psychological state of the patients was best at a calorie intake of180-240 Kcals/day.

I claim:
 1. A dietary formulation for the treatment of obesity in man,which comprises:(a) all the minerals required by man; (b) material whichis a source of aminoacids selected from at least one member of the classconsisting of:(i) a mixture of monomeric L-aminoacids, and (ii) naturalproteins, and (iii) natural proteins reinforced with at least onemonomeric L-aminoacid; and (c) digestible carbohydrate;characterized inthat a smallest amount of the dietary formulation containing at leastthe minimum daily requirements of each of the minerals required by man,including at least 800 mg calcium, 800 mg phosphorus, 140 μg iodine, 10mg iron and 350 mg magnesium, also contains (A) at least 15 g of saidmaterial which must include at least the minimum daily requirements forman of all the essential L-aminoacids required by man; and (B) from 15 gto 75 g of said carbohydrate;and further characterized in that the totalcaloric value of said smallest amount of the dietary formulation is inthe range of from 160 Kcals to 600 Kcals.
 2. A dietary formulationaccording to claim 1, in which the caloric value of said smallest amountof the formulation is not greater than 400 Kcals.
 3. A dietaryformulation according to claim 2, in which the caloric value of saidsmallest amount of the formulation is not greater than 360 Kcals.
 4. Adietary formulation according to claim 3, in which the caloric value ofsaid smallest amount of the formulation is in the range of from 180 to240 Kcals.
 5. A dietary formulation according to claim 1, in which saidsmallest amount of formulation includes the minimum daily requirementsof said minerals.
 6. A dietary formulation according to claim 1, inwhich the ratio by weight of said material to the digestiblecarbohydrate is in the range of from 1:2 to 1:3.
 7. A dietaryformulation according to claim 1, in which said material is or includesegg albumin.
 8. A dietary formulation according to claim 1, in whichsaid material is or includes natural protein derived from at least onemember of the class consisting of milk, soya beans, peanuts, fish andplasma.
 9. A dietary formulation according to claim 1, in which saidmaterial is or includes natural protein derived from at least one memberof the class consisting of milk, soya beans, peanuts, fish and plasma,reinforced with at least one monomeric aminoacid.
 10. A dietaryformulation according to claim 1, in which the carbohydrate componentcomprises a partially hydrolyzed polysaccharide.
 11. A dietaryformulation according to claim 10, in which the partially hydrolyzedpolysaccharide is an oligosaccharide having an average molecular weightof from 3 to 10 times that of the corresponding monomer.
 12. A dietaryformulation according to claim 11, in which the average molecular weightof the oligosaccharide is from 4 to 6 times that of the correspondingmonomer.
 13. A dietary formulation according to claim 1, in which thesaid smallest amount of the formulation includes at least the minimumdaily requirements of each of the vitamins required by man.
 14. Adietary formulation according to claim 13, in which said smallest amountof formulation includes the minimum daily requirements of each of saidvitamins.
 15. A dietary formulation according to claim 1, in which saidsmallest amount of the formulation includes at least the minimum dailyessential fatty acid requirements of man.
 16. A dietary formulationaccording to claim 15, in which the fatty acid is present in the form ofa highly unsaturated vegetable oil.
 17. A dietary formulation accordingto claim 16, in which the highly unsaturated vegetable oil is onecontaining at least 25% of linolenic acid.
 18. A dietary formulationaccording to claim 14, in which the said smallest amount of theformulation contains at least 2.4 g of fatty acid.
 19. A dietaryformulation according to claim 14, in which the fatty acid comprisesfrom 3 to 10% by weight of the formulation.
 20. A dietary formulationaccording to claim 1 wherein said smallest amount of the dietaryformulation contains 15 to 25 g of said material and 30 to 45 g of saidcarbohydrate.
 21. A dietary formulation for the treatment of obesity inman consisting essentially of:(a) all the minerals required by man; (b)material which is a source of aminoacids selected from at least onemember of the class consisting of:(i) a mixture of monomeric L-aminoacids, and (ii) natural proteins, and (iii) natural proteins reinforcedwith at least one monomeric L-amino acid; and (c) digestiblecarbohydrate;and characterized in that a smallest amount of the dietaryformulation containing at least the minimum daily requirements of saidminerals also contains: (A) at least 15 g of said material which mustinclude at least the minimum daily requirements for man of all theessential L-aminoacids required by man; and (B) from 15 to 75 g of saidcarbohydrate; and further characterized in that the total caloric valueof the smallest amount of the dietary formulation is in the range offrom 160 Kcals to 600 Kcals and in that the ratio by weight of saidmaterial to the digestible carbohydrate is in the range of 1:1 to 1:5.22. A dietary formulation according to claim 21 wherein said ratio is inthe range of from 1:2 to 1:4.
 23. A dietary formulation according toclaim 22 wherein the caloric value of said smallest amount of theformulation is not greater than 360 Kcals.
 24. A dietary formulationaccording to claim 21 wherein said smallest amount of the formulationcontains 15 to 25 g of said material, 30 to 45 g of said carbohydrate,and has a total caloric value of not greater than 360 Kcals.
 25. Adietary formulation according to claim 21 wherein the caloric value ofsaid smallest amount of the formulation is not greater than 400 Kcals.26. A dietary formulation according to claim 21 wherein the caloricvalue of said smallest amount of the formulation is not greater than 360Kcals.
 27. A dietary formulation according to claim 21 wherein thecaloric value of said smallest amount of the formulation is in the rangeof 180 to 240 Kcals.
 28. A formulation according to claim 21 whereinsaid smallest amount of dietary formulation containing at least theminimum daily requirements of the minerals required by man includes atleast 800 mg calcium, 800 mg phosphorous, 140 μg iodine, 10 mg iron and350 mg magnesium and also nutritional amounts of sodium, potassium,manganese, copper, zinc, chloride and sulfur.
 29. A low calorie dietaryformulation which is effective in providing an individual who ingests ona daily basis nothin more than said formulation with the minimum dailyamounts of all of the minerals and vitamins required by the individual,said formulation containing digestible carbohydrate and materials whichare sources of all of the essential L-aminoacids and all of theessential minerals required by an individual and characterized in thatsaid constituents are present in proportions such that an amount of theformulation which has a caloric value of 160 Kcals to 400 Kcals consistsessentially of:(A) at least 15 g of material which is a source ofaminoacids and selected from at least one member of the group consistingof: (i) a mixture of monomeric L-aminoacids; (ii) natural proteins; and(iii) natural proteins reinforced with at least one monomericL-aminoacid; said material including at least the minimum daily amountsof all the essential L-aminoacids required by an individual; (B) 15 to75 g of digestible carbohydrate; (C) mineral-containing material in anamount effective to provide said minerals in said amounts, including atleast 800 mg calcium, 800 mg phosphorus, 140 μg iodine, 10 mg iron, 350mg magnesium, and also nutritional amounts of sodium, potassium,manganese, copper, zinc, chloride, and sulfur; (D) about 2.4 to about3.8 g of fatty acid or material which is a source thereof; and (E)material which is a source of vitamins in an amount effective to providean individual with at least the minimum daily amounts of all of hisrequired vitamins, including at least 60 mg ascorbic acid (Vitamin C),0.4 mg folic acid, 18 mg niacin, 1.7 mg riboflavin, 1.4 mg thiamin, 5000i.u. Vitamin A, 2.0 mg Vitamin B₆, 5.0 μg Vitamin B₁₂, 400 i.u. VitaminD, and 30 i.u Vitamin E; andwherein the weight ratio of said material of(A) above to said digestible carbohydrate is in the range of 1:1 to 1:5.30. A formulation according to claim 29 including 15 to 25 g of saidmaterial of (A) and 30 to 45 g of said carbohydrate.
 31. A dietaryformulation which comprises:(a) material which is a source of aminoacidsselected from at least one member of the class consisting of:(i) amixture of monomeric L-aminoacids, and (ii) natural proteins, and (iii)natural proteins reinforced with at least one monomeric L-aminoacid; (b)digestible carbohydrate; and (c) calcium, phosphorous, iodine, iron andmagnesium;characterized in that a smallest amount of the dietaryformulation containing at least 800 mg calcium, 800 mg phosphorous, 140μg iodine, 10 mg iron and 350 mg magnesium, also contains (A) at least15 g of said material which must include at least the minimum dailyrequirements for man of all the essential L-aminoacids required by man;and (B) from 15 g to 75 g of said carbohydrate;and further characterizedin that the total caloric value of said smallest amount of the dietaryformulation is in the range of from 160 Kcals to 600 Kcals.
 32. Adietary formulation according to claim 31 in which the caloric value ofsaid smallest amount of the formulation is not greater than 400 Kcals.33. A dietary formulation according to claim 31 in which the caloricvalue of said smallest amount of the formulation is not greater than 360Kcals.
 34. A dietary formulation according to claim 31 in which theweight ratio of said material to said carbohydrate is in the range offrom 1:1 to 1:5.
 35. A dietary formulation according to claim 32 inwhich the weight ratio of said material to said carbohydrate is in therange of from 1:1 to 1:5.
 36. A dietary formulation according to claim33 in which the weight ratio of said material to said carbohydrate is inthe range of from 1:1 to 1:5.
 37. A dietary formulation according toclaim 31 in which the weight ratio of said material to said carbohydrateis in the range of from 1:2 to 1:4.
 38. A dietary formulation accordingto claim 32 in which the weight ratio of said material to saidcarbohydrate is in the range of from 1:2 to 1:4.
 39. A dietaryformulation according to claim 33 in which the weight ratio of saidmaterial to said carbohydrate is in the range of from 1:2 to 1:4.
 40. Aformulation according to claim 31, 32, 33, 34, 35, 36, 37, 38 or 39 andincluding also about 2.4 g to about 3.8 g of fatty acid or a materialwhich is a source thereof.
 41. A formulation according to claim 1, 21,or 31 in which the caloric content of said smallest amount of theformulation is in the range of 180 to 360 Kcals.
 42. A formulationaccording to claim 41 in which the weight ratio of said material to saidcarbohydrate is in the range of 1:1 to 1:5.